Bis[pyrrolyl Ru( <scp>ii</scp> )] triads: a new class of photosensitizers for metal–organic photodynamic therapy

Abstract

A new family of ten dinuclear Ru(ii) complexes based on the bis[pyrrolyl Ru(ii)] triad scaffold, where two Ru(bpy)₂ centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and <i>in vitro</i> photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(ii)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (<i>ε</i>) ≥ 10⁴ at 600-620 nm and longer. Phosphorescence quantum yields (<i>Φ</i> _p) were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields (<i>Φ</i> _Δ) ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC₅₀ values in the range of 10-100 μM and phototherapeutic indices (PIs) as large as 5400 and 260 with broadband visible (28 J cm^-2, 7.8 mW cm^-2) and 625 nm red (100 J cm^-2, 42 mW cm^-2) light, respectively. The bis[pyrrolyl Ru(ii)] triad with a pyrenyl linker (<b>5h</b>) was especially potent, with an EC₅₀ value of 1 nM and PI > 27 000 with visible light and subnanomolar activity with 625 nm light (100 J cm^-2, 28 mW cm^-2). The lead compound <b>5h</b> was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxicity in this more resistant model (EC₅₀ = 60 nM and PI > 1200 with 625 nm light) despite a lower dark cytotoxicity. The <i>in vitro</i> PDT effects of <b>5h</b> extended to bacteria, where submicromolar EC₅₀ values and PIs >300 against <i>S. mutans</i> and <i>S. aureus</i> were obtained with visible light. This activity was attenuated with 625 nm red light, but PIs were still near 50. The ligand-localized ³ππ* state contributed by the pyrenyl linker of <b>5h</b> likely plays a key role in its phototoxic effects toward cancer cells and bacteria.